rs727504336
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000257.4(MYH7):c.1477_1478del(p.Met493ValfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MYH7
NM_000257.4 frameshift
NM_000257.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.04
Genes affected
MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1477_1478del | p.Met493ValfsTer19 | frameshift_variant | 15/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.1477_1478del | p.Met493ValfsTer19 | frameshift_variant | 14/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1477_1478del | p.Met493ValfsTer19 | frameshift_variant | 15/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000410 AC: 6AN: 1461886Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727244
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 12, 2023 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Nov 30, 2021 | The NM_000257.3(MYH7):c.1477_1478delAT (p.Met493Valfs) variant has been identified in 1 individual with features of both HCM and DCM (Zimmerman 2010 PMID:20474083; Walsh 2017 PMID: 27532257, LMM pers. comm.) however, this is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; http:// gnomad.broadinstitute.org, v.2.1.1). This variant is predicted to cause a frameshift leading to a truncated or absent protein. The contribution of loss of function (LOF) variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood therefore PVS1 was not applied. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 26, 2016 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 177817). This premature translational stop signal has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 20474083, 27532257). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met493Valfs*19) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at